Down syndrome (DS) or trisomy for chromosome 21, is a major cause of mental retardation and congenital heart disease, that affects more than 400,000 individuals in the USA. In addition, people with DS have defects in memory, language and neuroanatomy. The ultimate goal of this proposal is to elucidate the genes, neuroanatomy and neurocircuitry linked to the neurocognitive defects of DS. Recent advances in human genome sequencing provide a complete list of chromosome 21 genes, but until recently (Korbel, 2009), there were no genes linked to any specific feature and no successful treatment for the cognitive deficits. Treatment of DS has been hindered by lack of human models for narrowing the genes responsible for cognitive features, the need for high resolution neuroimaging of the brain defects in DS and the need for cognitive tests focused on DS deficits. To address these gaps, we propose an innovative multidisciplinary approach integrating neuroimaging, cognitive testing and genetics. In DS as in genetics, rare events can illuminate common processes. Rare individuals have DS caused by duplication of only parts of chromosome 21 and provide a unique opportunity to link the defects of brain development and function with the genes responsible. The PI of this proposal has generated the largest cohort in existence, consisting of 45 persons, of whom 30 are alive, in the USA, 27 aneuploid only for 21. Recently, these rare cases were used to map specific gene subsets in DS for congenital malformations but little was known about the brain or cognition. Further, a unique and rare set of identical twins discordant for DS, has been identified and studied. To characterize these cohorts, a unique team of scientists has been created, with expertise in partial trisomy 21 (Korenberg), neurocognitive testing targeted to DS (Nadel, Yurgelun-Todd), Magnetic Resonance Imaging and Diffusion tensor imaging (Yurgelun- Todd, Gerig), NMR Spectroscopy (Renshaw) and genome organization (Korenberg). This team will integrate high resolution imaging of full and rare partial trisomy 21 to establish the regional neuroanatomy and neurocircuitry of DS and to link these to subsets of chromosome 21 genes. We will test three levels of hypotheses, first to define in DS vs normals, distinct volumetric and circuit brain structures and defects of cognitive function, including language and memory; second, to link within DS, neural substrates with cognitive features and third, by using each rare partial trisomy, to begin to parse gene subsets for DS neural and cognitive features. Further, we will test in DS, whether the glutamatergic or, as in mouse, the GABAergic neurotransmitter systems are disturbed in vivo. We propose two aims: 1) to characterize 60 normal and 60 full trisomy 21 individuals with cognitive testing, high resolution MRI, DTI and MRS, 2) to characterize the rare DS cohort with partial trisomy 21 and the unique set of identical twins discordant for DS as in aim 1. The results of these studies will provide unprecedented knowledge of the defects of brain development and function in DS, GABAergic and glutamatergic pathways, and the relationship of both to genes duplicated. These results will help to elucidate the neurobiology of DS and to develop novel treatments for DS and other intellectual disabilities.